Effect of osteocalcin on sarcopenic obesity

• Project/Area Number: 18K09521
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57010:Oral biological science-related
• Research Institution: Kyushu University
• Principal Investigator: Mizokami Akiko 九州大学, 歯学研究院, 准教授 (70722487)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: オステオカルシン / 脂肪分解 / 肥満 / 酸化ストレス / インスリン抵抗生 / 骨格筋 / サルコペニア肥満 / インスリン抵抗性 / サルコペニア

Outline of Final Research Achievements

Uncarboxylated osteocalcin (GluOC) is a bone-derived hormone that plays an important role not only in glucose and energy metabolism but also in maintaining skeletal muscle mass. GPRC6A, a member of family C of G protein-coupled receptors, has been reported to serve as a GluOC receptor. We analyzed adipocyte-specific GPRC6A deficient mice and found that these animals manifested adipocyte hypertrophy under obesogenic environment. This was associated with reduced lipolytic activity due to down-regulation of lipolytic enzymes in adipose tissue of the knockout mice. Suppressed lipolysis resulted in reduced fatty acid release in the circulation compared with control mice. Our results suggest that the constitutive activation of GPRC6A signaling by GluOC in adipocytes plays a key role in lipolysis, providing fatty acid as an energy source to the skeletal muscle.

Academic Significance and Societal Importance of the Research Achievements

サルコペニア肥満は、代謝異常と運動機能低下の悪循環によって、サルコペニアや肥満の単独事象よりも深刻な身体機能低下をもたらし、要介護・寝たきりのリスクが高まる。GluOCは、脂肪細胞におけるGPRC6Aシグナルを介して脂肪の分解を促進する。つまり、GluOCは食餌誘発性の肥満とそれに起因する代謝異常を抑制するのみならず、脂肪分解促進作用による遊離脂肪酸放出によって骨格筋にエネルギー源を供給し、骨格筋の機能向上にも寄与する。GluOCはサルコペニアと肥満の両方にアプローチすることでサルコペニア肥満の悪循環を断ち切る治療標的となり得る。

Research Products

• [Journal Article] Phospholipase C-related but catalytically inactive protein acts as a positive regulator of insulin signalling in adipocytes. (2022)
  • Author(s): Gao, J., Mizokami, A., Takeuchi, H., Li, A., Huang, F., Nagano, H., Kanematsu, T., Jimi, E., Hirata, M.
  • Journal Title: J. Cell. Sci. Volume: 135 Issue: 1
  • DOI: 10.1242/jcs.258584
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] オステオカルシンのホルモン作用 (2022)
  • Author(s): 溝上 顕子、安河内（川久保）友世、大谷 崇仁、平田 雅人
  • Journal Title: 糖尿病・内分泌代謝科 Volume: 54(3) Pages: 259-266
• [Journal Article] Hepatic glycogenolysis is determined by maternal high-calorie diet via methylation of Pygl and it is modified by oteocalcin administration in mice (2021)
  • Author(s): Kawakubo-Yasukochi Tomoyo、Yano Ena、Kimura Soi、Nishinakagawa Takuya、Mizokami Akiko、Hayashi Yoshikazu、Hatakeyama Yuji、Ohe Kenji、Yasukochi Atsushi、Nakamura Seiji、Jimi Eijiro、Hirata Masato
  • Journal Title: Molecular Metabolism Volume: 54 Pages: 101360-101360
  • DOI: 10.1016/j.molmet.2021.101360
  • Peer Reviewed / Open Access
• [Journal Article] Osteocalcin promotes proliferation, differentiation, and survival of PC12?cells (2021)
  • Author(s): Ando Eika、Higashi Sen、Mizokami Akiko、Watanabe Seiji、Hirata Masato、Takeuchi Hiroshi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 557 Pages: 174-179
  • DOI: 10.1016/j.bbrc.2021.03.146
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis (2021)
  • Author(s): Mukai Satoru、Mizokami Akiko、Otani Takahito、Sano Tomomi、Matsuda Miho、Chishaki Sakura、Gao Jing、Kawakubo-Yasukochi Tomoyo、Tang Ronghao、Kanematsu Takashi、Takeuchi Hiroshi、Jimi Eijiro、Hirata Masato
  • Journal Title: Journal of Biological Chemistry Volume: 296 Pages: 100274-100274
  • DOI: 10.1016/j.jbc.2021.100274
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The roles of osteocalcin in lipid metabolism in adipose tissue and liver (2020)
  • Author(s): Otani Takahito、Mizokami Akiko、Kawakubo-Yasukochi Tomoyo、Takeuchi Hiroshi、Inai Tetsuichiro、Hirata Masato
  • Journal Title: Advances in Biological Regulation Volume: 78 Pages: 100752-100752
  • DOI: 10.1016/j.jbior.2020.100752
  • Peer Reviewed / Open Access
• [Journal Article] GLP-1 signaling is required for improvement of glucose tolerance by osteocalcin. J. Endocrinol. (2020)
  • Author(s): Mizokami, A., Mukai, S., Gao, J., Kawakubo-Yasukochi, T., Otani, T., Takeuchi, H., Jimi, E., Hirata, M.
  • Journal Title: Journal of Endocrinology Volume: 244 Issue: 2 Pages: 285-296
  • DOI: 10.1530/joe-19-0288
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phospholipase C-related catalytically inactive protein regulates lipopolysaccharide-induced hypothalamic inflammation-mediated anorexia in mice (2019)
  • Author(s): Yamawaki Yosuke、Shirawachi Satomi、Mizokami Akiko、Nozaki Kanako、Ito Hikaru、Asano Satoshi、Oue Kana、Aizawa Hidenori、Yamawaki Shigeto、Hirata Masato、Kanematsu Takashi
  • Journal Title: Neurochemistry International Volume: 131 Pages: 104563-104563
  • DOI: 10.1016/j.neuint.2019.104563
  • Peer Reviewed / Open Access
• [Journal Article] Osteocalcin triggers Fas/FasL-mediated necroptosis in adipocytes regulated by the activation of p300. (2018)
  • Author(s): Otani, T., Matsuda, M., Mizokami, A., Kitagawa, N., Takeuchi, H., Jimi, E.,Inai, T., and Hirata, M.
  • Journal Title: Cell Death Disease Volume: 9 Issue: 12 Pages: 1194-1210
  • DOI: 10.1038/s41419-018-1257-7
  • Peer Reviewed / Open Access
• [Presentation] 脂肪細胞表面受容体GPRC6による脂質代謝制御 (2021)
  • Author(s): 溝上顕子、大谷崇仁、兼松隆、自見英治郎、平田雅人
  • Organizer: 第６３回歯科基礎医学会学術大会
  • Invited
• [Presentation] 閉経による血清RANKL 濃度の上昇はNF-κBの非古典的経路を活性化し肥満を引き起こす (2021)
  • Author(s): 森馨代、溝上顕子、佐野朋美、兼松隆、自見英治郎
  • Organizer: 第６３回歯科基礎医学会学術大会
• [Presentation] 脂肪組織炎症でCCL19-CCR7経路が制御するmicroRNAの同定 (2021)
  • Author(s): 佐野朋美、Elsheikh Malaz、溝上顕子、兼松隆
  • Organizer: 第６３回歯科基礎医学会学術大会
• [Presentation] Role of glucagon-like peptide-1 receptor signaling in osteocalcin-mediated improvement of whole-body metabolism (2020)
  • Author(s): 溝上 顕子
  • Organizer: 第62回 歯科基礎医学会学術大会
  • Invited
• [Presentation] Adipose tissue-specific knockout of GPRC6A promotes diet-induced obesity by inhibiting lipolysis (2020)
  • Author(s): 溝上 顕子，大谷 崇仁, 松田 美穂, 安河内 友世, 竹内 弘，自見英治郎，平田 雅人
  • Organizer: 第62回 歯科基礎医学会学術大会
• [Presentation] Adipocyte-specific GPRC6A ablation induces diet-induced obesity by inhibiting lipolysis. (2019)
  • Author(s): Akiko Mizokami, Satoru Mukai, Takahito Otani, Hiroshi Takeuchi, Eijiro Jimi, and Masato Hirata
  • Organizer: 2019 International Congress on Obesity and Metabolic Syndrome & Asia-Oceania Conference on Obesity (ICOMES & AOCO 2019)
  • Int'l Joint Research
• [Presentation] オステオカルシンの代謝改善効果における GLP-1 受容体シグナルの役割 (2019)
  • Author(s): 溝上 顕子，向井 悟，竹内 弘，自見英治郎，平田 雅人
  • Organizer: 第61回歯科基礎医学会学術大会
• [Presentation] 脂肪細胞表面受容体GPRC6Aを介した脂肪蓄積機構 (2018)
  • Author(s): 溝上顕子、松田美穂、竹内弘、安河内友世、自見英治郎、平田雅人
  • Organizer: 第60回歯科基礎医学会学術大会
  • Invited
• [Presentation] Protective effect by uncarboxylated osteocalcin against UVB-induced reactive oxygen species in HaCaT keratinocytes. (2018)
  • Author(s): 溝上顕子、久保山奈緒、向井悟、高靖、自見英治郎、平田雅人
  • Organizer: 第91回日本生化学会大会
• [Presentation] Programmed necrosis of adipocytes induced by high-dose osteocalcin (2018)
  • Author(s): Otani T, Hirata M, Mizokami A, Kitagawa N, Jimi E. and Inai T.
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research